Cargando…
The Legs at odd angles (Loa) Mutation in Cytoplasmic Dynein Ameliorates Mitochondrial Function in SOD1(G93A) Mouse Model for Motor Neuron Disease
Amyotrophic lateral sclerosis (ALS) is a debilitating and fatal late-onset neurodegenerative disease. Familial cases of ALS (FALS) constitute ∼10% of all ALS cases, and mutant superoxide dismutase 1 (SOD1) is found in 15–20% of FALS. SOD1 mutations confer a toxic gain of unknown function to the prot...
Autores principales: | , , , , , , , , , , , |
---|---|
Formato: | Texto |
Lenguaje: | English |
Publicado: |
American Society for Biochemistry and Molecular Biology
2010
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2881788/ https://www.ncbi.nlm.nih.gov/pubmed/20382740 http://dx.doi.org/10.1074/jbc.M110.129320 |
_version_ | 1782182137023168512 |
---|---|
author | El-Kadi, Ali Morsi Bros-Facer, Virginie Deng, Wenhan Philpott, Amelia Stoddart, Eleanor Banks, Gareth Jackson, Graham S. Fisher, Elizabeth M. C. Duchen, Michael R. Greensmith, Linda Moore, Anthony L. Hafezparast, Majid |
author_facet | El-Kadi, Ali Morsi Bros-Facer, Virginie Deng, Wenhan Philpott, Amelia Stoddart, Eleanor Banks, Gareth Jackson, Graham S. Fisher, Elizabeth M. C. Duchen, Michael R. Greensmith, Linda Moore, Anthony L. Hafezparast, Majid |
author_sort | El-Kadi, Ali Morsi |
collection | PubMed |
description | Amyotrophic lateral sclerosis (ALS) is a debilitating and fatal late-onset neurodegenerative disease. Familial cases of ALS (FALS) constitute ∼10% of all ALS cases, and mutant superoxide dismutase 1 (SOD1) is found in 15–20% of FALS. SOD1 mutations confer a toxic gain of unknown function to the protein that specifically targets the motor neurons in the cortex and the spinal cord. We have previously shown that the autosomal dominant Legs at odd angles (Loa) mutation in cytoplasmic dynein heavy chain (Dync1h1) delays disease onset and extends the life span of transgenic mice harboring human mutant SOD1(G93A). In this study we provide evidence that despite the lack of direct interactions between mutant SOD1 and either mutant or wild-type cytoplasmic dynein, the Loa mutation confers significant reductions in the amount of mutant SOD1 protein in the mitochondrial matrix. Moreover, we show that the Loa mutation ameliorates defects in mitochondrial respiration and membrane potential observed in SOD1(G93A) motor neuron mitochondria. These data suggest that the Loa mutation reduces the vulnerability of mitochondria to the toxic effects of mutant SOD1, leading to improved mitochondrial function in SOD1(G93A) motor neurons. |
format | Text |
id | pubmed-2881788 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2010 |
publisher | American Society for Biochemistry and Molecular Biology |
record_format | MEDLINE/PubMed |
spelling | pubmed-28817882010-06-10 The Legs at odd angles (Loa) Mutation in Cytoplasmic Dynein Ameliorates Mitochondrial Function in SOD1(G93A) Mouse Model for Motor Neuron Disease El-Kadi, Ali Morsi Bros-Facer, Virginie Deng, Wenhan Philpott, Amelia Stoddart, Eleanor Banks, Gareth Jackson, Graham S. Fisher, Elizabeth M. C. Duchen, Michael R. Greensmith, Linda Moore, Anthony L. Hafezparast, Majid J Biol Chem Molecular Bases of Disease Amyotrophic lateral sclerosis (ALS) is a debilitating and fatal late-onset neurodegenerative disease. Familial cases of ALS (FALS) constitute ∼10% of all ALS cases, and mutant superoxide dismutase 1 (SOD1) is found in 15–20% of FALS. SOD1 mutations confer a toxic gain of unknown function to the protein that specifically targets the motor neurons in the cortex and the spinal cord. We have previously shown that the autosomal dominant Legs at odd angles (Loa) mutation in cytoplasmic dynein heavy chain (Dync1h1) delays disease onset and extends the life span of transgenic mice harboring human mutant SOD1(G93A). In this study we provide evidence that despite the lack of direct interactions between mutant SOD1 and either mutant or wild-type cytoplasmic dynein, the Loa mutation confers significant reductions in the amount of mutant SOD1 protein in the mitochondrial matrix. Moreover, we show that the Loa mutation ameliorates defects in mitochondrial respiration and membrane potential observed in SOD1(G93A) motor neuron mitochondria. These data suggest that the Loa mutation reduces the vulnerability of mitochondria to the toxic effects of mutant SOD1, leading to improved mitochondrial function in SOD1(G93A) motor neurons. American Society for Biochemistry and Molecular Biology 2010-06-11 2010-04-09 /pmc/articles/PMC2881788/ /pubmed/20382740 http://dx.doi.org/10.1074/jbc.M110.129320 Text en © 2010 by The American Society for Biochemistry and Molecular Biology, Inc. Author's Choice—Final version full access. Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) applies to Author Choice Articles |
spellingShingle | Molecular Bases of Disease El-Kadi, Ali Morsi Bros-Facer, Virginie Deng, Wenhan Philpott, Amelia Stoddart, Eleanor Banks, Gareth Jackson, Graham S. Fisher, Elizabeth M. C. Duchen, Michael R. Greensmith, Linda Moore, Anthony L. Hafezparast, Majid The Legs at odd angles (Loa) Mutation in Cytoplasmic Dynein Ameliorates Mitochondrial Function in SOD1(G93A) Mouse Model for Motor Neuron Disease |
title | The Legs at odd angles (Loa) Mutation in Cytoplasmic Dynein Ameliorates Mitochondrial Function in SOD1(G93A) Mouse Model for Motor Neuron Disease |
title_full | The Legs at odd angles (Loa) Mutation in Cytoplasmic Dynein Ameliorates Mitochondrial Function in SOD1(G93A) Mouse Model for Motor Neuron Disease |
title_fullStr | The Legs at odd angles (Loa) Mutation in Cytoplasmic Dynein Ameliorates Mitochondrial Function in SOD1(G93A) Mouse Model for Motor Neuron Disease |
title_full_unstemmed | The Legs at odd angles (Loa) Mutation in Cytoplasmic Dynein Ameliorates Mitochondrial Function in SOD1(G93A) Mouse Model for Motor Neuron Disease |
title_short | The Legs at odd angles (Loa) Mutation in Cytoplasmic Dynein Ameliorates Mitochondrial Function in SOD1(G93A) Mouse Model for Motor Neuron Disease |
title_sort | legs at odd angles (loa) mutation in cytoplasmic dynein ameliorates mitochondrial function in sod1(g93a) mouse model for motor neuron disease |
topic | Molecular Bases of Disease |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2881788/ https://www.ncbi.nlm.nih.gov/pubmed/20382740 http://dx.doi.org/10.1074/jbc.M110.129320 |
work_keys_str_mv | AT elkadialimorsi thelegsatoddanglesloamutationincytoplasmicdyneinamelioratesmitochondrialfunctioninsod1g93amousemodelformotorneurondisease AT brosfacervirginie thelegsatoddanglesloamutationincytoplasmicdyneinamelioratesmitochondrialfunctioninsod1g93amousemodelformotorneurondisease AT dengwenhan thelegsatoddanglesloamutationincytoplasmicdyneinamelioratesmitochondrialfunctioninsod1g93amousemodelformotorneurondisease AT philpottamelia thelegsatoddanglesloamutationincytoplasmicdyneinamelioratesmitochondrialfunctioninsod1g93amousemodelformotorneurondisease AT stoddarteleanor thelegsatoddanglesloamutationincytoplasmicdyneinamelioratesmitochondrialfunctioninsod1g93amousemodelformotorneurondisease AT banksgareth thelegsatoddanglesloamutationincytoplasmicdyneinamelioratesmitochondrialfunctioninsod1g93amousemodelformotorneurondisease AT jacksongrahams thelegsatoddanglesloamutationincytoplasmicdyneinamelioratesmitochondrialfunctioninsod1g93amousemodelformotorneurondisease AT fisherelizabethmc thelegsatoddanglesloamutationincytoplasmicdyneinamelioratesmitochondrialfunctioninsod1g93amousemodelformotorneurondisease AT duchenmichaelr thelegsatoddanglesloamutationincytoplasmicdyneinamelioratesmitochondrialfunctioninsod1g93amousemodelformotorneurondisease AT greensmithlinda thelegsatoddanglesloamutationincytoplasmicdyneinamelioratesmitochondrialfunctioninsod1g93amousemodelformotorneurondisease AT mooreanthonyl thelegsatoddanglesloamutationincytoplasmicdyneinamelioratesmitochondrialfunctioninsod1g93amousemodelformotorneurondisease AT hafezparastmajid thelegsatoddanglesloamutationincytoplasmicdyneinamelioratesmitochondrialfunctioninsod1g93amousemodelformotorneurondisease AT elkadialimorsi legsatoddanglesloamutationincytoplasmicdyneinamelioratesmitochondrialfunctioninsod1g93amousemodelformotorneurondisease AT brosfacervirginie legsatoddanglesloamutationincytoplasmicdyneinamelioratesmitochondrialfunctioninsod1g93amousemodelformotorneurondisease AT dengwenhan legsatoddanglesloamutationincytoplasmicdyneinamelioratesmitochondrialfunctioninsod1g93amousemodelformotorneurondisease AT philpottamelia legsatoddanglesloamutationincytoplasmicdyneinamelioratesmitochondrialfunctioninsod1g93amousemodelformotorneurondisease AT stoddarteleanor legsatoddanglesloamutationincytoplasmicdyneinamelioratesmitochondrialfunctioninsod1g93amousemodelformotorneurondisease AT banksgareth legsatoddanglesloamutationincytoplasmicdyneinamelioratesmitochondrialfunctioninsod1g93amousemodelformotorneurondisease AT jacksongrahams legsatoddanglesloamutationincytoplasmicdyneinamelioratesmitochondrialfunctioninsod1g93amousemodelformotorneurondisease AT fisherelizabethmc legsatoddanglesloamutationincytoplasmicdyneinamelioratesmitochondrialfunctioninsod1g93amousemodelformotorneurondisease AT duchenmichaelr legsatoddanglesloamutationincytoplasmicdyneinamelioratesmitochondrialfunctioninsod1g93amousemodelformotorneurondisease AT greensmithlinda legsatoddanglesloamutationincytoplasmicdyneinamelioratesmitochondrialfunctioninsod1g93amousemodelformotorneurondisease AT mooreanthonyl legsatoddanglesloamutationincytoplasmicdyneinamelioratesmitochondrialfunctioninsod1g93amousemodelformotorneurondisease AT hafezparastmajid legsatoddanglesloamutationincytoplasmicdyneinamelioratesmitochondrialfunctioninsod1g93amousemodelformotorneurondisease |